Order of events for endothelial signaling in leukocyte extravasation. (1) Leukocyte firm adhesion mediated by β2-integrins induces clustering of endothelial ICAM-1 and its association with actin-binding proteins (such as α-actinin⁴ and cortactin^1,8). (2) This mediates reorganization of cortical F-actin to promote local stiffening with concomitant increased tension. (3) Flow and local tension cooperate to activate PIEZO1. (4) The increase in intracellular calcium triggers activation of SRC and PYK2 and induces, through phosphorylation of myosin light chain (pMLC), actomyosin contraction, disrupting vascular endothelial (VE)-cadherin complexes in cell-cell contacts. (5) Local loss of VE-cadherin–mediated adhesion drives its internalization and (6) efficient leukocyte migration across the endothelial barrier. Professional illustration by Somersault 18:24.